ABSTRACT Patients with Alzheimer?s disease (AD), a neurogenerative disorder resulting in dementia, accumulate beta- amyloid (A?) plaques. Recently, it has been shown that this accumulation of A? results in the downregulation of the ubiquitin ligase known as the Anaphase-Promoting Complex/Cyclosome (APC), leading to an accumulation of its substrates, excitotoxicity, and apoptosis. However, a mechanistic understanding of how the deregulation of the APC contributes to AD is unclear. We aim to dissect this process using a comprehensive approach involving enzyme kinetics, cell-based assays, and mouse models in to understand which APC substrates are elevated in AD (Aim 1) and how can we reactivate the APC in AD mouse models (Aim 2). Based on preliminary data funded by the existing MIRA, we have uncovered a novel mechanism of APC activation that could be harnessed to rescue the downregulation of APC activity observed in AD. Therefore, this project specifically relates to the Notice of Special Interest: Alzheimer?s-focused administrative supplements for NIH grants that are not focused on Alzheimer?s disease, for multiple reasons. First, Dr. Brown is an early career investigator with expertise in the regulation of and by the APC. As the APC is paramount in the signaling of the Spindle Assembly Checkpoint, which is the focus of funded MIRA, Dr. Brown is ideally suited to apply his reagents and techniques to examine the role of the APC in AD. Second, he will firmly establish a new collaboration with an accomplished investigator in the AD field Dr. Juan Song, who will mentor Dr. Brown to address a significant basic science gap. Taken together, information generated from the proposed research will stimulate additional activities, solidify a new collaboration for an R01 proposal in the future, provide a foundation for a new structural biologist to enter the AD field, and may enable the development of novel AD therapeutics.